1. Field of the Invention
The present invention relates to a new process for the production of a 9,3"-di-acyl derivative of a macrolide antibiotic containing a tertiary 3"-hydroxyl group which has been acylated, i.e. esterified, by an alkanoic acid.
2. Description of the Prior Art
Generally, many of the useful macrolide antibiotics contain a mycarose moiety therein, and they include, for example, leucomycins, midecamycin, angolamycin, spiramycins, carbomycin, megalomicin and the like. All of these macrolide antibiotics contain a tertiary hydroxyl group at the 3"-position of the molecule, and it is known that the tertiary hydroxyl group cannot be acylated with a conventional agent for acylating a hydroxyl group.
It has been difficult to acylate or esterify a tertiary alcohol because of the unreactivity of the tertiary hydroxyl group. Processes for the acylation of the tertiary alcohol are known, for example, the method of conducting the acylation in the presence of 4-dimethylaminopyridine ("Angewandte Chemie" Vol. 81, p 1001 (1969) W. Steglich, G, Hofle) and the method of conducting the acylation in the presence of 1-methyl-2-halopyridinium salt ("Chemistry Letter" p. 1045 (1975) T. Mukaiyama, M. Usui, E. Shimada). In these prior art methods, however, the acylation product cannot be obtained in a reasonable yield without using an expensive acylation reagent.
Midecamycin, one of the known macrolide antibiotics, is initially known as the SF-837 substance (see U.S. Pat. No. 3,761,588 and the "Journal of Antibiotics" Vol. 29, No. 5, pages 536-548 (1976)), and various acyl (particularly alkanoyl) derivatives of midecamycin are provided (see U.S. Pat. Nos. 3,761,588; 3,792,035; 3,855,202; 3,959,256 and 4,017,607, for instance). Midecamycin contains three free hydroxyl groups at the 9-, 2'-, and 3"-positions of the molecule. The 9- and 2'-hydroxyl groups of midecamycin are relatively reactive while the tertiary 3"-hydroxyl group thereof is less reactive for the acylation (i.e., esterification) with an alkanoic acid or its halide or anhydride derivative which is usually employed as the agent for acylating an alcohol, and there is not known a process of directly acylating the tertiary 3"-hydroxyl group of midecamycin with an alkanoic acid or its functional derivative such as the acid halide and acid anhydride.
According to the process of U.S. Pat. No. 4,017,607, it is possible to produce a 9,3"-di-alkanoyl derivative of medicamycin by reacting medicamycin with an alkanoic acid anhydride in the presence of an organic base such as pyridine, picoline or triethylamine in a first step to produce a 9,2',4"-trialkanoyl-3"-propionyl SF-837 M.sub.1 substance optionally together with a 9,18,2',4"-tetra-alkanoyl-3"-propionyl SF-837 M.sub.1 substance, and then partially and selectively hydrolyzing these acylation products in an aqueous alkanol in a second step to remove a 2'-alkanoyl group and optionally the 18-alkanoyl group therefrom. However, this two-step process of U.S. Pat. No. 4,017,607 inevitably involves the concurrent and intramolecular shift of the initially existing 4"-propionyl group to the 3"-hydroxyl group in the acylation step, so that the 3"-hydroxyl group initially present in the midecamycin molecule cannot be acylated directly by the alkanoic acid anhydride which is employed as the acylation agent. Besides, this process requires the presence of an organic base in the first step thereof, and this organic base can cause contamination of the final product.
An object of the present invention is to provide a new process which is able to produce a 9,3"-di-alkanoyl midecamycin having an alkanoyl group other than the propionyl group at the 3"-position thereof, independent of the nature of the starting material. Another object of the present invention is to provide a new process of producing a 9,3"-di-alkanoyl midecamycin in which the 3"-hydroxyl group of the starting midecamycin or its derivative employed is esterified directly with the alkanoyl group of the acylating agent employed. A generic object of the present invention is to provide a new process which is able to directly acylate the tertiary hydroxyl group of a macrolide antibiotic containing such tertiary hydroxyl group.